(3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids and derivatives thereof, processors for their preparation and pharmaceutical compositions containing them

ABSTRACT

The invention relates to novel compounds of formula (I) wherein R is a hydrogen atom or a C 1  -C 5  alkyl group and R 2  is selected from the group consisting of: (a) a straight-chained or branched C 5  -C 12  alkyl radical; (b) a group --O--R 4 , wherein R 4  is a straight-chained or branched C 2  -C 9  alkyl radical which may be substituted at the terminal carbon atom by a phenyl group; (c) a group --(CH 2 ) n  --O--alkyl, wherein n is an integer of from 1 to 7 and the alkyl group contains from 1 to 5 carbon atoms, having the (3S,4S) configuration, essentially free of the (3R,4R) enantiomer. The invention also relates to process for the preparation of compounds of formula (I) as defined above. The invention further relates to pharmaceutical compositions which possess analgesic, anti-inflammatory, anti-emetic, anti-glaucoma, leukocytes antiadhesion or PAF activity, containing as active ingredient compounds of formula (I) as defined above.

This application is a 371 of PCT/U.S.92/07718, filed Sep. 11, 1992.

FIELD OF THE INVENTION

The present invention relates to(3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids and homologs andderivatives thereof, essentially free of the (3R,4R) form, and toprocesses for their preparation. The invention also relates topharmaceutical compositions containing said compounds as activeingredients, having anti-inflammatory, analgetic, leucocyteanti-adhesion, antiplatelet activating factor (PAF), and anti-glaucomaactivities, as well as properties effective in alleviating certainsymptoms due to neuronal injury or loss.

BACKGROUND OF THE INVENTION

The (3S,4S) enantiomers of cannabimimetically active cannabinoids, suchas the natural (3R,4R)-delta-1-tetrahydrocannabinol (THC) are generallynot cannabimimetic. This lack of undesirable CNS side effects makes themsuitable candidates as therapeutic agents. It has been previously shownthat the (3S,4S)-7-hydroxy-delta-6-tetrahydrocannabinol1,1-di-methylheptyl homolog (compound 1a in the appended Figures) is ananalgetic, entiemetic and anti-NMDA drug [U.S. Pat. No. 4,876,276;Mechoulam, R., et al., Tetrahedron: Asymmetry, 1, 315 (1990);Feigenbaum, J. J., et al., Proc. Natl. Acad. Sci., 86, 9584 (1989)]. Ithas also been shown that (3R,4R)-delta-1-tetrahydrocannabinol-7-oic acid(compound 2), which also shows no psychotropic effects, is ananti-inflammatory and analgetic compound [U.S. Pat. No. 4,847,290].However, the (3S,4S)-tetrahydrocannabinol-7-oic acids have not yet beenprepared and their therapeutic activity has been unknown so far. Thesecompounds have now been synthesized and were found to possess unexpectedtherapeutically important properties.

SUMMARY OF THE INVENTION

The present invention relates to(3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids, homologs andderivatives thereof having the general formula: ##STR2## wherein R is ahydrogen atom or a C₁ -C₅ alkyl group, R¹ is a hydrogen atom or a C₁ -C₅acyl group and R² is selected from the group consisting of: (a) astraight-chained or branched C₅₋ C--₁₂ alkyl; (b) a group --O--R₄,wherein R₄ is a straight-chained or branched C₂ -C₉ alkyl which may besubstituted at the terminal carbon atom by a phenyl group; and (c) agroup --(CH₂)_(n) --O--alkyl, where n is an integer of from 1 to 7 andthe alkyl group contains from 1 to 5 carbon atoms.

The most preferred compounds are the 1,1-dimethylheptyl (DMH) homologsof (3S,4S)-(+)-delta-6-tetrahydrocannabinol-7-oic acid (hereafterdesignated HU-235, compound 3a in the appended FIG. 1) and its acetate(hereafter designated HU-245, compound 3c in FIG. 1).

It is stressed that all the compounds are of the (+)-(3S,4S)configuration, essentially free of the (-)-(3R,4R) enantiomer. Thecompounds of the type defined by general formula (I) are substantiallydevoid of "cannabis-type" CNS activity.

The invention also relates to processes for the preparation of compoundsof general formula (I).

FIG. 1 illustrates the reaction pathways of the processes of theinvention.

In a first embodiment the process for the preparation of a compound offormula (I) wherein R is a hydrogen or a C₁ -C₅ alkyl group and R¹ andR² are as defined in claim 1, comprises:

(a) reacting a compound of the formula: ##STR3## wherein Y is astraight-chained or branched C₁ -C₅ alkyl, X is a suitable protectivegroup and R² is as defined in formula I with a suitable reducing agentto give the corresponding allylic alcohol of formula III: ##STR4## (b)oxidizing the alcohol of formula III with a suitable oxidizing agent togive the corresponding aldehyde of formula IV: ##STR5## (c) oxidizingthe aldehyde of formula IV with a suitable oxisizing agent to give thecorresponding allylic acid of formula V: ##STR6## and (d) removing theprotective group X to give the acid according to formula (I).

Y can be, for example, (trimethyl)methyl.

In stage (a) the protective group OY may optionally be replaced by thegroup --NR⁴ R⁵, wherein R⁴ and R⁵ are C₁ -C₅ alkyl groups.

The phenolic protective groups X can be, for example,dimethyl-tert.-butylsilyl, or other silyl derivatives such asphenylsilyl, a C₁ -C₅ alkyl group or benzyl. These alkyl or benzylethers, which serve as protective groups to the phenol ring, can laterbe removed by standrd procedures.

The reducing agent can be, for example, lithium aluminum hydride.

In a second embodiment compounds of general formula (I) wherein thesubstituents are as defined above may be prepared as follows:

(a) subjecting a compound of the formula: ##STR7## wherein R² is asdefined above to selective esterification, to give the correspondingphenolic ester of formula VII: ##STR8## wherein R³ is a C₁ -C₅ alkyl, orbenzyl which may be substituted at the para position by chlorine orbromine;

(b) oxidizing the ester of formula VII with a suitable oxidizing agentto give the corresponding aldehyde of formula VIII: ##STR9## (c)oxidizing the aldehyde of formula VIII with a suitable oxidizing agentto give the corresponding acid of formula I: ##STR10## optionallyremoving the ester group COR³ to give the corresponding compound:##STR11##

According to a first embodiment, the pathway of which is illustrated inFIG. 1, the starting material is7-hydroxy-delta-6-tetrahydrocannabinol-DMH(1a) (HU-211) (which may beprepared according to the procedure reported by Mechoulam, R., et al.,Tetrahdron: Asymmetry, 1,315 (1990)), protected at the 7-position byconventional protective groups, for example pivalate (compound 1b), thephenolic group also being protected by a conventional protective group,for example dimethyltert.butylsilyl (compound 4b). This protectedstarting material is reduced, for example, by lithium aluminum hydride,to give the corresponding allylic alcohol (compound 4a). The alcohol isthen oxidized, for example with chromic oxide in pyridine, to give thecorresponding aldehyde (compound 5b). Other oxidizing agents, forexample, tert.-butyl chromate, chromic acid/pyridine complex or relatedchromate derivatives or manganese dioxide, particularly in the presenceof cyanide, or related manganese derivatives may be used. The aldehydeis further oxidized, for example with sodium chlorite, to give thecorresponding allylic acid (compound 3b). Other oxidizing agents such asmanganese dioxide in the presence of sodium cyanide and acetic acid andrelated manganese derivatives may be used. The phenolic protective groupis then removed, to give the desired acid (compound 3a, HU-235). Thissynthetic route may yield a series of related compounds which wereprepared.

The second embodiment also uses7-hydroxy-delta-6-tetra-hydrocannabinol-DMH (Compound 1a) as thestarting material. This starting material is subjected to selectiveesterifacation to give the monoacetate (compound 4c), which on oxidationwith, for example, chromic acid in pyridine gives the aldehyde (compound5d), which is further oxidized to the acid (compound 3c, HU-245). Otheroxidizing agents, as above, may be used. Removal of the phenolicprotective group leads to the desired acid (compound 3a, HU-235).

The invention also relates to pharmaceutical compositions which possesspotent analgetic, anti-inflammatory, anti-emetic, anti-galucoma,anti-platelet activating factor and leukocyte anti-adhesion activities,containing compounds of general formula (I) as active ingredient. Thesecompositions also reduce and may even prevent excitatory amino acidneurotoxicity due to acute injury to the central nervous system, such asinjuries due to prolonged epileptic seizures, compromised or reducedblood supply, deprivation of glucose supply and mechanical trauma. Thecompositions are of special value in grand mal seizure, global hypoxicischemic insults, in hypoxia, alonr or in combination with blood flowreduction (ischemia), as well as in cases of abrupt occlusion ofcerebral arteries (stroke). The compositions of the present inventionmay also be effective in alleviating certain chronic degenerativediseases associated with gradual selective neuronal loss, mainlyHuntington's chorea, Parkinsonism and Alzheimer's disease. Thecompositions of the present invention have also been discovered to beeffective in the treatment of multiple sclerosis. The compositions ofthe present invention are also useful in the treatment of poisoningaffecting the central nervous system, for example strychnine, picrotoxinor organophosphorous poisoning.

The novel compositions contain in additin to the active ingredientconventional pharmaceutically acceptable carriers, diluents and thelike. Solid compositions for oral administration such as tablets, pills,capsules or the like may be prepared by mixing the active ingredientwith conventional, pharmaceutically acceptable ingredients such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesiumstearate, dicalcium phosphate and gums with pharmaceutically acceptablediluents. The tablets or pills can be coated or otherwise compoundedwith pharmaceutically acceptable materials known to provide a dosageform affording prolonged action or sustained release. Other solidcompositions can be prepared as suppositories for rectal administration.Liquid forms may be prepared for administration or for injection, theterm including sub-cutaneous, transdermal, intravenous, intratechal,etc. administration. The liquid compositions include aqueous solutions,flavored syrups, aqueous or oil suspensions, flavored emulsions withedible oils, as well as elixirs and similar pharmaceutical vehicles. Inaddition, the compositions of the present invention may be formed asaerosol, for intra-nasal and like administration.

The active dose for humans is generally in the range of from 0.005 mg toabout 50 mg per kg body weight, in regimen of 1-4 times a day. However,administration every two days may also be possible, as the drug has arather prolonged action. The preferred range of dosage is from 1.0 mg toabout 20 mg per kg body weight. However, it is evident to the manskilled in the art that dosages would be determined by the attendingphysician, according to the disease to be treated, method ofadministration, patient's age, weight, counterindications and the like.

All the compounds defined above are effective in treating the aboveconditions and can be used as active ingredients of pharmaceuticalcompositions for treatment of one, or simultaneously several, of thesymptoms or disorders defined above. The effective dosages areessentially similar.

The invention also relates to use of the compositions of the presentinvention for the treatment of the various pathological conditionsdescribed above. Administration of therapeutically effective amounts ofthe compositions of the present invention as used herein encompassesoral, parenteral, intravenous, intramuscular, sub-cutaneous,transdermal, intratechal, rectal and intra-nasal administration.

PREPARATORY EXAMPLES

1. Synthesis of the Dimethyl-tert-butylsilyl ether (4a).

The ester (1b) (2.9g, 6.17 mmoles), [α]D +152.6° (c, 17.2 mg/ml, CHCl₃),was dissolved in dry dimethylformamide (DMF) (6 ml.).Dimethyl-tert-butylsilyl chloride (1.85 g, 12.27 mmoles) and imidazole(1.67 g, 24.6 mmoles) were added and the resulting mixture was stirredfor 48 hours at 38° C. Water (30 ml) was added and the mixture wasextracted with ether. After evaporation of the dried ether layer an oil(4b) (3.6 g) was obtained; [α]D+153° (c, 24.45 mg/ml, CHCl₃); I.R. max(neat) 1725 cm⁻¹. No free hydroxyl groups were observed; ¹ H NMR δ(CDCl₃) 3.28 (1H, br d, J=16 Hz, C-2 equat. H), 4.46 (2H, s, C-7H,),5.70 (1H, m, C-6H,), 6.38 (1H, d, J-1.5 Hz, arom.), 6.42 (1 H, d, J=1.5Hz, arom). This oil (compound 4b) was used in the next step with nofurther purification.

A solution of compound (4b) (3.2 g, 5.5 mmoles) in dry ether (50 ml) wasadded under a nitrogen atmosphere to lithium aluminum hydride (870 mg)in dry ether (60 ml). The resulting mixture was boiled under reflux for1.5 hours. After the usual work up (ethyl acetate followed by slowaddition of a saturated solution of magnesium sulphate until a clearether supernatant is formed) the ether layer was dried and evaporated togive an oil (3.2 g). The oil was chromatographed on a silica gel column(100 g), using ether:petroleum ether (6:4) as eluent, to give thealcohol (4a) (8 g, 67%); [α]D +175°; (7.6 mg/ml, CHCl₃) I.R. max (neat)3320 cm⁻¹ (OH band); no carbonyl bands; 1H NMR δ (CDCl₃) δ 3.38 (1 H, brd, J=16 Hz, C-2 equat. H) 4.02 (2 H, s, C-7 H), 5.72 (1 H, br d, C-6 H),6.36, 6.42 (2 H, s, aromatic).

2. Synthesis of Aldehyde (5b).

Dry pyridine (2.3 ml), followed by chromic oxide (1.44 g, 14.4 mmoles)were added to a solution of methylenechloride: DMF (4:1) (36 ml). Themixture was stirred for 15 min. The primary allylic hydroxy compound(4a) (1.8 g, 3.6 mmoles) in methylchloride: DMF (4:1) (7.2 ml) was addedand the reaction mixture was stirred at room temp. for 1 hr. Ethanol(1.8 ml) was added, the mixture was stired for additional 10 min., andwas then diluted with ethylacetate (180 ml). The resulitng mixture wasfiltered through a sintered glass funnel, packed with silica (3 cm),with a layer of anhydrous sodium sulfate on top, and eluted with ethylacetate (ca 600 ml). The ethyl acetate filtrate was washed with dilutehydrochloric acid (1N), then with sodium bicarbonate solution and water.After evaporation of the dried organic solvent a semi-solid compound(5b) (1.7 g, 95%) was obtained. Crystallization from pentane gave thealdehyde (5b); m.p. 80°-81° C.; [α]-268° (C, 6.82 mg/ml, CHCl₃); I.R.max 1690 cm⁻¹ (neat); 1H NMR δ (CDCl₃) 3.82 (1 H, br d, J=15 Hz, C-2equat. H), 6.38 and 6.42 (2H, s, aromatic), 6.80 (1 H, m, C-6 H), 9.50(1 H, s, c-7 H). Anal. (C₃₁ H₅₀ O₃ Si) C H.

3. Synthesis of (3S,4S)-delta-6-THC-DMH-7-oic acid (3a).

Sodium chlorite (488 mg) was added portionwise with vigorous stirring toa mixture of the aldehyde (5b) (498 mg, 1 mmole), 2-methyl-2-butene(2.24 ml), saturated aqueous potassium dihydrogenphosphate (1.34 ml) andt-butanol (22 ml). The reaction mixture was stirred at room temp. for 5hrs. Water (20 ml) was added and the mixture was extracted several timeswith enthyl acetate, dried and evaporated to give the crude acid whichwas purified on a silica gel column (10 g, elution with 10%ether:pet.ether) to give the acid (3b) (460 mg, 89%) as an oil; [α]^(D)+218° (c, 13.7 mg/ml, CHCl₃); I.R. max 1680, cm⁻¹ ; and a broad band inthe 2800-3600 region; ¹ H NMR δ 3.75 (1 H, br d, J=18 Hz, C-2 equat. H),6.23 (1 H, d, J=1.5, arom.), 6.27 (1 H, d, J=1.5, arom.), 7.00 (1 H, m,c-6 H).

Tetrabutylammonium fluoride (0.6 mmoles solution in THF) was added byinjection under a nitrogen atmosphere to a cold solution (ice bath) ofthe acid (3b) (280 mg, 0.54 mmoles) in tetrahydrofuran (THF) (3 ml). Theresulting solution was stirred at 0° for 15 minutes. Water was added andthe mixture extracted several times with ether. The ether layer wasdried and evaporated to give the crude product. The product was furtherpurified on a silica gel column with ether:petroleum ether (1:1) aseluent. The solid thus obtained (140 mg, 56%) was crystallized fromacetronitrile to give the acid (3a) m.p. 112-114 (sintering); [α]^(D)+275° (c, 3.8 mg/ml, CHCl₃), I.R. max (Nujol) 1680 cm⁻¹ and a broad bandin the 3100-3600 region; 1H NMR δ 3.82 (1 H, br d, J=18 Hz, C-2 equat.H), 6.22 (1 H, d, J=1.5 Hz, arom.) 6.38 (1 H, d, J=1.5 arom). 7.16 (1 H,m, C-6 H); m/z 400 (M). The acetate (3c), (HU-245), melts at 120°-122°;[α]^(D) +265° (c, 9.0 mg/ml, CHCl₃) I.R. max (Nujol) 1760 cm⁻¹ and abroad band in the 3100-3600 cm⁻¹ region; ¹ H NMR (CDCl₃) 6 2.30 (3 H, s,OCOCH₃), 3.38 (1 H, br d, J=19 Hz, C-2 equat. H), 6.56, (1 H, d, J=1.5Hz atom.) 6.68 (1 H, d, j=1.5 arom.), 7.18 (1 H, m, C-6 H). Anal. (C₂₇H₃₈ O₅) C, H. The methyl ether (3d) melts at 172°-174°; [α]^(D) +270°(7.5 mg/ml, CHCl₃); I.R. max (KBr) 1660, 1680 cm⁻¹ and a broad band inthe 3100-3600 region; (CHCl₃) 1696 cm⁻¹ ; ¹ H NMR (CDCl₃) 3.76 (1 H, brd, J=18 Hz, C-2 equat. H), 3.80 (3 H, s, OCH₃), 6.39, 6.42, (2 H, s,aromatic), 7.16 (1 H, m, C-6H); MS m/z 414 (M⁺). Anal. (C₂₆ H₃₈ O₄) C,H.

4. Synthesis of Aldehyde (5a).

Tetrabutylammonium fluoride (0.4 mmoles, soln. in THF) was added, byinjecton to a cold solution (ice bath) of the aldehyde (5b) (200 mg, 0.4mmoles-) in THF (4 ml), under a nitrogen atmosphere. The solution wasstitred at 0° C. for 5 minutes and then at room temperature for 15minutes. The solvent was evaporated and the residue was separated on asilica gel column (10 g). The product was eluted with ether:petroleumether (15:85). The solid obtained (120 mg, 78%) was crystallized frompentane to give the required compound (5a) m.p. 174°-175°; I.R. max.(KBr) 1690 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 3.84 (1 H, d J=17 Hz, C-2/equat. H),6.24, 6.36 (2 H, s, aromatic), 6.86 (1 H, m, C-6 H), 9.48 (1 H, s, C-7H). Anal. (C₂₅ H₃₆ O₃) C, H. The methyl ether (5c) melts at 109°-110°;[α]^(D) +302 (c, 8.2 mg/ml, CHCl₃); I.R. max (neat) 1680 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 3.76 (1 H, d, J=18 Hz, C-2 equat. H) 3.80 (3 H, s, OCH3),6.38, (1H, d, J=1.5, arom.), 6.42 (1 H, d, J=1.5, atom.), 6.82 (1 H, m,C-6 H), 9.50 (1 H, s, C-7 H); MS m/z 398 (M⁺). Anal. (C₂₆ H₃₈ O₃) C, H.

5. Synthesis of HU-211, Monoacetate (4c).

Potassium (1 g) was added to 2-methyl-2-butanol (16 ml) under a nitrogenatmosphere. The mixture was warmed, at 80°, until all the metal hadreacted. The excess alcohol was removed by vacuum distillation and thedry residue was dissolved in dry benzene (45 ml). Two ml of thissolution were added to HU-211 (300 mg, 0.78 mmoles) dissolved in drybenzene (30 ml). The solution was stirred, under a nitrogen atmosphere,for 2 hrs., then it was washed with a dilute HCl solution (1N), followedby a sodium bicarbonate solution (1N) and then with water. The organiclayer was dried over MgSO₄, and evaporated. The oil obtained waschromatographed on silica gel (15 gr.) Elution with ether:petroleumether (1:10) gave the diacetate of HU-211 (99 mg) followed by traces ofthe monoacetate (on the allylic alcohol moiety), eluted withether:petroleum ether (2:10), followed by the monoacetate (4c), 150 mg,identified by the I.R. peak at 1760 cm⁻¹ ; ¹ H NMR δ2.28 (3H, s,OCOCH₃), 2.98 (1H, dd, C-2 equat. H), 4.02 (2H, q, C-7 H), 5.72 (1H, d,C-6 H), 6.52, 6.66 (atom. H).

6. Synthesis of Aldehyde (5d).

Dry pyridine (0.645 ml, 8 mmol) was added to methylene chloride:DMF(4:1), followed by chromic oxide (400 mg, 4 mmol). The mixture wasstirred at toom temp. for 15 min. The ester (4c) (430 mg, 1 mmol) in theabove solvent mixture (2 ml) was added and the reaction mixture wasstirrred at room temperatue for 16 hrs., then diluted with ethyl acetate(50 ml) and filtered through a sintered glass funnel covered with a 3 cmlayer of silica, with a layer (1 cm) of anhydrous magnesium sulphateover it. Ethyl acetate (200 ml) was passed through this double layer;the solvents were evaporated and the residue was chromatographed onsilica, using ether:petroleum ether (1:5), yielding the aldehyde (5d)280 mg (66%) as an oil, identified by the I.R. peaks at 1760 cm⁻¹(phenolic acetate) and 1680 cm⁻¹ (unsaturated aldehyde); ¹ H NMR δ2.20(3H, s, OCOCH₃), 2.82 (1H, dd, C-2 equat. H), 6.42, 6.58 (arom. H), 6.70(C-6 H), 9.40 (aldehyde H). This aldehyde was used without furtherpurification.

7. Synthesis of (3S,4S)-THC-DMH-7-oic Acid, Acetate (3c) (Hu-145).

Sodium chlorite (488 mg, 4.3 mmol) was added portionwise with vigorousstirring to a mixture of the aldehyde (5d) (4.26 mg, 1 mmole),2-methyl-2-butene (2.24 ml, 21 mmole), saturated sodium hydrogenphosphate (1.34 ml) and t-butanol (22 ml). The reaction mixture wasstirred for 5 h. at room temp., extracted with ethyl acetate, dried overmagnesium sulphate and the solvent was removed. The acid obtained (390mg, 88%), m.p. 120°-122° (from pentane) was identical to the materialdescribed above.

PHARMACOLOGICAL EXAMPLES

1. Relief of Edema Induced by Arachidonic Acid and PAF.

The induction of paw edema in rodents by injection of arachidonic acidhas been used as an experimental model for inflammation [Calhoun, W., etal., Agents and Actions, 21, 306 (1987)]. Prior administration ofnon-steroidal anti-inflammatory drugs (NSAIDs) in many cases leads to adose related inhibition of the edematous response which may beconsidered a predictor of clinical efficacy. The cannabinoid acidHU-235, and related compounds were effective in reducing paw edema inthis model as seen in Table 1.

A second model, in which edema is induced by platelet activating factor(PAF), was used to evaluate activity. As may be seen from the resultssummarized in Table II, the acid HU-235 and related compounds were foundto be active.

The conditions were based on those reported previously [Calhoun et al.,ibid.]. Water was substituted for mercury as the displacement medium andwas found to give satisfactory results. PAF (1.0 μg) or arachidonic acid(1.0 mg) dissolved in 50 μl of 5% ethanol in saline, were injected s.c.into the plantar surface of the right hind paw of CD-1 female mice(20-25 g) obtained from Charles River Labs. The mice were under etheranesthesia during this procedure. The volume of the right foot wasmeasured to the level of the lateral malleous by water displacementbefore treatment and 15 min after PAF injection or 30 min afterarchidonate injection. The change in paw volume was calculated for eachmouse and the significance for each group was determined by a paired ttest analysis.

                  TABLE I                                                         ______________________________________                                        Inhibition of Arachidonic Acid-Induced Paw Edema.sup.1                        Dose (mg,kg).sup.2                                                                      HU-245 (3c)                                                                              7a        7b   HU-235(3a)                                ______________________________________                                        0.050     35.7 (N.S.)                                                                              5.5 (N.S.)                                                                              48.5 42.1 (N.S.)                               0.100     50.1*      10.2 (N.S.)                                                                             66.2*                                                                              65.8*                                     0.250     48.2*      40.1 (N.S.)                                                                             51.4*                                                                              52.6*                                     0.55      42.2 (N.S.)                                                                              47.2*     48.2*                                                                              47.4                                      ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Inhibition of PAF-Induced Paw Edema.sup.3                                             Dose mg/kg.sup.4                                                      Treatment 0.05      0.10   0.25 0.5   1.0   40.0                              ______________________________________                                        HU-235 (3a)                                                                             44.4 (N.S.)                                                                             38.7*  31.9*                                                                              60.1* --    --                                HU-245 (3c)         37.3*  66.9*                                                                              72.0* --    --                                7b                  39.0*  59.0*                                                                              68.2* --    --                                HU-211 (1a)         --     --   37.5  21.9  --                                                                (N.S.)                                                                              (N.S.)                                  Δ.sup.6 -THC-7-oic                                                                          --     --   --    --    50.2                              acid                                                                          ______________________________________                                         .sup.1 Values shown are percent inhibition of paw edema when compared to      vehicle treated controls.                                                     *95% significance by ANOVA. N.S.  nonsignificant.                             .sup.2 Control mice were given peanut oil (50 μl) orally.                  .sup.3 Values shown are percent inhibition of paw edema when compared to      vehicle treated controls.                                                     *95% significance by ANOVA. (analysis of variance) N.S.  nonsignificant.      .sup.4 Control mice were given peanut oil (50 μl) orally).            

2. Decreased Adhesion of Leukocytes.

Leukocytes are thought to be major contributors to the inflammatoryresponse and their ability in this regard is reflected by theiradhesiveness to a variety of substrates [Audette, C.A., et al., LifeSci., 47, 753 (1990)]. The data in Table III show that peritoneal

leukocytes from mice orally administered with the present cannabinoidsexhibit decreased adhesion.

The details of the leukocytes adhesion assay have been previouslyreported [Audette et al., ibid.]. In brief, peritoneal cells from femalsCD-1 mice (20-25 g) were collected at 90 min following oraladministration of the drug or vehicle (50 μl peanut oil). Cells fromeach treatment group (N=3) were pooled and equal numbers aliquoted intosix culture dish wells (1.9 cm² area). After incubation for 18-20 hours,non-adhering cells were removed and the remaining cell monolayerquantitated by DNA measurement.

                                      TABLE III                                   __________________________________________________________________________    Effects of Leukocyte Adhesion.sup.5                                           __________________________________________________________________________    Dose (mg/kg).sup.6                                                                     HU-211(1a)                                                                              HU-245(3c)                                                                              235(3a)                                          Control  0.88 ± 0.08(100)                                                                     1.26 ± 0.05(100)                                                                     1.26 ± 0.05(100)                              0.01     --        --        1.34 ± 0.14(106)                              0.05     1.09 ± 0.08(124)*                                                                    1.32 ± 0.04(105)                                                                     1.29 ± 0.05(102)                              0.10     0.44 ± 0.03(50)*                                                                     0.66 ± 0.05(52)*                                                                     1.38 ± 0.17(110)                              0.20     --        --        --                                               0.50     0.64 ± 0.06(73)*                                                                     0.85 ± 0.08(67)*                                                                     1.46 ± 0.05(116)                              1.00     0.59 ± 0.06(67)*                                                                     0.30 ± 0.04(24)*                                                                     0.70 ± 0.12(56)*                              THC-7-oic Acid                                                                Control  0.81 ± 0.03-                                                      20       0.67 ± 0.02(90.6)*                                                40       0.55 ± 0.22(67.9)*                                                __________________________________________________________________________     .sup.5 Values are the number of adhering cells × 10.sup.-6 ± S.D     Numbers in parentheses are percent of control. For details see                Experimental Section.                                                         *95% significance by ANOVA; otherwise not statistically significant.          .sup.6 Control mice were given 50 μl peanut oil orally. Peritoneal         cells were collected 90 min after oral administration of cannabinoids.   

3. Antinociception.

As with many NSAID type drugs, the present cannabinoids also showedactivity in the mouse hot plate test (55° C.) for antinociception.

In the hot plate test for analgesia an aluminum surface was maintainedat 55°±1° C. by circulating water through passages in the metal. A clearplastic cylinder 18 cm in diameter and 26 cm high was placed on thesurface to prevent escape. The end point was taken when the mouse eitherperformed a hind paw lick or jumped off the surface; in no case were theanimals kept for more than 30 secs on the plate. Mice were never usedmore than one time; control values were always measured at 11 a.m. andtest values at 2 p.m. The drugs were administered orally 90 min beforethe hot plate test. The percent change in response time (latency) wascalculated by comparing the mean of the control values with the mean ofthe test values and statistical signficance determined by a pairedt-test analysis using software (Statview, 512) from Brainpower, Inc.,Calabasas, Calif.

                  TABLE IV                                                        ______________________________________                                        ANTINOCIOPCEPTIVE EFFECTS.sup.7                                               Dose (mg/kg)                                                                            HU211 (1a)                                                                              3e       HU-245(3c)                                                                            HU-235(3a)                               ______________________________________                                        0.025      --        --      10.7(5) 10.3(5)                                  0.050      --        --      66.2(5)*                                                                              61.7(5)*                                 0.10       --        --      62.2(5)*                                                                              49.5(20)*                                0.25      30.0(5)*  10.4(5)  68.1(10)*                                                                             61.5(17)**                               0.50      72.5(5)***                                                                              49.0(10)*                                                                              49.9(5)*                                                                              51.7(8)*                                 1.0       -10.2(5)  61.4(15)*                                                                              12.5(5) 14.7(5)                                  2.0        --       37.5(10)          --                                      4.0        --       3.1(10)   --      --                                      ______________________________________                                         .sup.7 Values are the percent change in latency. See above for details.       Figures in brackets are the number of mice.                                   *P < 0.05;                                                                    **P < 0.005 by a paired t test; otherwise not statistically significant. 

4. Cataleptic Effects.

The lack of CNS activity for the compounds described herein may be seenfrom the data shown in Table V. This was measured by the so-called "ringtest" [Pertwee, R. G., et al., J. Pharmacol., 46, 753 (1972)] in whichthe cataleptic effects of cannabinoids can be quantitated. The compoundsproduced little or no response when compared with the parent drug.

The cataleptic response was measured using the ring test. Mice wereplaced on a horizontal wire ring 5.5 cm in diameter, which was attachedto a 16 cm vertical rod. The hind paws and fore paws were placed atopposite sides of the ring. It is important that the ambient temperatureis maintained at 30° C. and that the environment be free of auditorystimuli and bright lights. The criteria for immobility are detailed byPertwee. The response is calculated as the fraction of time the mouse isimmobile over a 5-min test period. Measurements were always done between2 and 4 p.m. and the animals were used only once.

                  TABLE V                                                         ______________________________________                                        CATALEPTIC EFFECTS IN THE MOUSE.sup.8                                         Treatment    Dose (mg/kg)                                                                              Response ± SD                                     ______________________________________                                        Vehicle.sup.9                                                                              --          7.7 ± 4.4                                         HU-245 (3c)  0.5         6.8 ± 2.4                                         HU-245 (3c)  1.0         12.0 ± 6.0                                        HU-235 (3a)  0.25        12.3 ± 10.3                                       HU-235 (3a)  0.5         13.8 ± 7.9                                        HU-235 (3a)  1.0         10.4 ± 10.6                                       HU-235 (3a)  4.0         8.7 ± 5.6                                         Δ.sup.1 -THC                                                                         40          48.9 ± 16*                                        ______________________________________                                         .sup.8 The values are expressed as the means of the fraction of time the      mice remained immobile ± SD. See above for other details.                  *95% signficance by ANOVA; otherwise not statistically significant.           .sup.9 Peanut oil (50 μl) given orally.                               

5. Neuroprotection.

The present compounds are active in several tests generally used toindicate neuroprotection. For example, HU-245 which was investigatedmost thoroughly, is a blocker of N-methyl-D-aspartate (NMDA) andpicrotoxin induced lethality in mice, as seen previously for HU-211(compound 1a). It also protects against strychnine induced lethality inrats. Compounds HU-211 (1a), HU-235 (3a) and HU-245 (3c) have also beenshown to protect against forebrain ischemia (unilateral occlusion) inmongolian gerbils.

Ba1a/c male mice were administered with the drug 90 min before treatmentwith NMDA (125 mg/kg) or 120 min before picrotoxin (8 mg/kg) inemulsion, s.c. The survival rate shown in Table VI indicates number ofsurvivors out of total number of animals used.

                  TABLE VI                                                        ______________________________________                                        Toxin       Drug           Survival rate                                      ______________________________________                                        Picrotoxin  --             0/17                                               Picrotoxin  HU-245 (10 mg/kg)                                                                            5/8                                                Picrotoxin  HU-211 (10 mg/kg)                                                                            6/10                                               Picrotoxin  HU-235 (10 mg/kg)                                                                            8/12                                               NMDA        --             0/20                                               NMDA         HU-245 (2.5 mg/kg)                                                                          6/12                                               NMDA        HU-245 (10 mg/kg)                                                                            8/10                                               NMDA        HU-235 (10 mg/kg)                                                                            7/10                                               NMDA        HU-211 (10 mg/kg)                                                                            11/16                                              ______________________________________                                    

6. Anti-Glaucoma Activity.

Reduction of intraocular pressure in rabbits was determined by theaddition of a 50 μl drop of a 1% emulsion of the cannabinoid into therabbit eye. This test is a measure of anti-glaucomatic activity.Significant reduction was established for compounds HU-235 and Hu-245.

7. NMDA-blocking Response in Oocytes.

The oocyte is the most widely used system for studying the molecular,biophysical and pharmacological properties of expressed voltage- ortransmitter-operated ion channels. This giant cell offers severaladvantages for this type of studies. It can be readily used fortwo-electrode voltage clamp studies, translates injected mRNA fromdifferent sources and functionally expresses the translated proteins,and it is also readily amenable for intracellular microinjections.Importantly, the recordings of transmitter- or voltage-incuded currentsin a single oocyte are extremely stable and can be done, withoutrundown, for 2-3 hours; this allows the performance of a fulldose-response relation in single oocytes.

Neuronal receptors for excitatory amino acid (EAA) are becomingincreasingly important for the understanding of normal and pathologicalbrain function. Quantitative pharmacological studies of EAA receptor/ionchannel complex are difficult to study in neurons. Therefore, Xenopusoocyte injected with brain mRNA is now the preparation of choice.

The response to N-methyl-D-aspartate (NMDA) in oocytes injected with ratbrain mRNA was characterized and the effects of HU-245 were studied.

Female Xenopus were anesthetized by immersion in water containing 0.15%tricaine methanesulfonate and a small incision was made in the loweradbomen. Ovary fragments were removed into ND-96. The frog was allowedto heal for at least three months before using again.

The oocytes were defolliculated by the collagenase treatment in order toremove the follicle cell layer. Defolliculated oocytes were injectedwith total rat brain RNA and incubated for 2-4 days at 22° C. in sterileNDE-96 solution. ND-96 solution contains (in mM): NaCl 96, KCl 2, CaCl₂1.8, Hepes 5 (pH=7.4-7.6). NDE-96 contains in addition, 2.5 mM sodiumpyruvate, 100 unit/ml penicillin, 100 μg/ml streptomycin.

A single oocyte was placed in a 1 ml bath constantly superfused withND-96 solution at room temperature. The cell was impaled with twomicroelectrodes and held at membrane potential of -60mV using voltageclamp circuit.

RNA was extracted from brain of 14-day old rat brain. Each oocyte wasinjected with 50 nl total RNA (4-8 mg/ml in water, stored at -80° C. in3-10 nl aliquots).

All chemicals were from Sigma.

Oocytes injected with rat brain RNA became responsive to all EAA (NMDA,kainate, glutamate) and to other transmitters (5HT, GABA, etc.). Theconductance activated by NMDA was examined more closely. In most oocytesNMDA alone did not evoke any detectable currents, and the addition ofglycine was necessary in order to evoke a response. Therefore, toobserve an NMDA response, the combination: 10⁻⁴ M NMDA AND 5×10⁻⁶ Mglycine was used in all the experiments.

Several NMDA receptor blockers were tested. These compounds have verylow solubility and have to be dissolved in 100% dimethyl sulfoxide(DMSO) and diluted for use in ND 96 that contained 1% DMSO. Therefore,the effect of 1% DMSO on the response to 10⁻⁴ M NMDA and 5×10⁻⁶ Mglycine was examined. DMSO had no effect on NMDA response in threedifferent cells.

The new derivative HU-245 was tested on the NMDA response at aconcentration of 10⁻⁶ M. A complete blocking effect could not beachieved since the compound is only soluble at a concentration of up to10⁻⁷ M. Compound HU-245 had a strong inhibitory effect on the responseto NMDA-55% of control at 10^(-6M). Another advantage of HU-245 seems tobe its solubility, which is higher than that of prior art compounds. Theeffect of HU-245 was reversible upon return to ND 96 solution.

We claim:
 1. A compound of the formula: ##STR12## wherein R is ahydrogen atom or a C₁ -C₅ alkyl group, R¹ is a hydrogen atom or a C₁ -C₅alkanoyl group, and R² is a 1,1-dimethyl heptyl group, said compoundhaving the (3S,4S) configuration, essentially free of the (3R,4R)enantiomer.
 2. A compound of general formula (I) being the1,1-dimethylheptyl homolog of(+)-(3S,4S)-delta-6-tetrahydrocannabinol-7-oic acid.
 3. A compound ofgeneral formula (I) being the 1,1-dimethylheptyl homolog of(3S,4S)-(+)-delta-6-tetrahydrocannabinol-7-oic acid, acetate.
 4. Apharmaceutical composition comprising as active ingredient a compound ofgeneral formula (I) according to claim
 1. 5. A pharmaceuticalcomposition according to claim 16 wherein the active ingredient is the1,1-dimethyl-heptyl homolog of(3S,4S)-(+)-delta-6-tetrahydrocannabinol-7-oic acid.
 6. A pharmaceuticalcomposition according to claim 16 wherein the active ingredient is the1,1-dimethylheptyl homolog of(3S,4S)-(+)-delta-6-tetrahydrocannabinol-7-oic acid, acetate. 7.Pharmaceutical compositions according to any one of claims 4 to 6 indosage unit form.
 8. A method of treating inflammation, pain or glaucomawhich comprises administering to a patient a therapeutically effectiveamount of a pharmaceutical composition according to any one of claims 4to
 6. 9. A method of treating acute injuries to the central nervoussystem associated with excitatory amino acid neurotoxicity whichcomprises administering to a patient a therapeutically effective amountof a pharmaceutical composition according to any claims 4 to 6.